Ether anesthetic agent

ABSTRACT

THE METHOD INDUCING ANESTHESIA BY ADMINISTERING AN ANESTHETICALLY EFFECTIVE AMOUNT OF DIFLUORO 1,2,2,3,3-PENTAFLOROPROPYL ETHER.

United States Patent 3,769,428 ETHER ANESTHETIC AGENT Bernard M. Regan, Chicago, Ill., assignor to Baxter Laboratories, Inc., Morton Grove, 1]]. No Drawing. Original application Aug. 10, 1970, Ser. No. 62,679, now Patent No. 3,689,459, dated Sept. 5, 1972. Divided and this application July 3, 1972, Ser. No.

Int. Cl. A61k 27/00 US. Cl. 424-342 1 Claim ABSTRACT OF THE DISCLOSURE The method inducing anesthesia by administering an anesthetically effective amount of difluoro 1,2,2,3,3-pentae fluoropropyl ether.

This is a divisional application of application Ser. No. 62,679, filed Aug. 10, 1970, now U.S. Pat. No. 3,689,459.

The present invention relates to the novel organic compound difluoromethyl 1,2,2,3,3-pentafluoropropyl ether, CI-IF OCHFCF CHF and to its method of use as a general anesthetic agent.

A closely related isomer, CF -OCH -C-F -CI-LF has been described by Aldrich and Sheppard, J. Org. Chem., vol. 29, pp. 11-15 (1964), to be a highly lethal convulsant agent when inhaled by mice at 0.5 volume percent concentrations. Another closely related isomer, CHF O-CH -CF -CF has now been found to be convulsant and non-anesthetic in mice. Furthermore, a precursor, CHF -O'CH CF CHF to the compound of this invention also has now been found to be a convulsant agent and devoid of anesthetic activity in mice. Therefore, the discovery that the present compound, CHF OCHF-CF -CHF has excellent anesthetic properties in warmblooded, air breathing animals was surprising and unexpected.

The novel anesthetic compound of this invention provides smooth anesthesia in mice. It is highly potent, having a median anesthetic concentration (AC of 0.61 volume percent, and has a high margin of safety (LC A0 of 6.5 upon inhalation in admixture with air for five to ten minutes. (LC =median lethal concentration.)

Repeated inhalation anesthesia with the present com pound was well tolerated by a dog (15 kilogram male beagle). On each of five successive days anesthesia was induced with 6 volume percent in oxygen and then maintained with 2 volume percent for the duration of each three hour exposure. Anesthesia was maintained each day at a depth sufiicient to abolish response to pain. No signs of subacute or cumulative toxicity were produced. Body weight was maintained at about 15 kilograms throughout the five day period of anesthesia. No evidence of any cardiac arrhythmia or bradycardia was observed. Blood pressure stabilized at about 100/60 during the three hour maintenance period on the first day of anesthesia. Respiratory rate usually stabilized at about ten breaths per minute and respiratory minute volume stabilized at two liters per minute. Electroencephalograms (EEG) were normal during maintenance of anesthesia. Periods of burst supresssion observed on the frontal-occipital EEG after prolonged exposure to an anesthetic concentration of 6 volume percent were abolished by lowering the concentration to 2 volume percent.

The anesthetic compound of this invention is non-flammable in air and non-explosive in oxygen or nitrous oxide. Its lower flammability limits (LF-L) with fl'ame ignition are about 7.9 volume percent in oxygen and about 9.7 volume percent in nitrous oxide.

The present anesthetic compound is stable to soda-lime as determined by gas-liquid chromatography (GLC).

Therefore, it is eminently suitable for use in anesthetic procedures which employ soda lime for the absorption of carbon dioxide.

Difluoromethyl 1,2,2,3,3-pentafluoropropyl ether is a colorless, volatile liquid which boils at a temperature of about 74.5 C. at 760 torr and has a density of about 1.55 grams/ml. at 20 C. It has a pleasant ethereal odor.

The novel anesthetic compound of this invention can be prepared according to the general reaction scheme as follows:

CHFiCl all Cl: Av

CHFr-O-CHCl-C Fn-CHF! CHFg-O-C Cir-C Fa-CHF:

II III BlFal lBrFa In the above reaction scheme, 2 ,2,3,3-tetrafluoropropanol and chlorodifluoromethane are converted in the presence of strong alkali, for example, sodium hydroxide or potassium hydroxide, to the novel difluoromethyl ether 1. From about 1.5 to about 2.0 moles of CHF Cl and about 5 moles of NaOH or KOH per about one mole of the alcohol are preferred. The reaction temperature preferably is from about 5 C. to about 25 C. In carrying out this reaction, it is advantageous to employ a mutual solvent, for example, a water-miscible, relatively high boiling, non-reactive solvent such as diethyleneglycol dimethylether.

The ether I can be chlorinated 'with a chlorinating agent such as chlorine or sulfuryl chloride in the presence of ultraviolet light to obtain the novel chloroether II. From about 0.5 to about 1.5 moles of chlorine per mole of I and a reaction temperature of from about 15 C. to about 30 C. are preferred.

It is preferable to free II of I before proceeding to convert II to the novel anesthetic Compound IV of this invention, since I and IV are diflicult to separate by fractional distillation as their boiling points differ by only 1 C. A secondary chlorination product, essentially the new dichloroether III, is diflicult to separate from II by fractional distillation.

The novel anesthetic Compound IV of the present invention can be prepared by exchange of chlorine for fluorine between the chloroether II and bromine trifluoride. From about one-third to about one-half mole of BrF per about one mole of II and a reaction temperature of from about 25 C. to about 60 C. are preferred.

Mixtures of chloroether II and dichloroether III can v EXAMPLE 1 Difiuoromethyl 2,2,3,3-tetrafluoropropyl ether (I) 2,2,3,S-tetrafluoropropanol (520 grams) was added to a stirred mixture (at 5 C.) of sodium hydroxide (790 3 grams), water (1240 ml.) and diethyleneglycol dimethylether (1880 ml.) in a stirred reactor fitted with a Dry Ice cooled condenser. Then chlorodifiuoromethane (565 grams) was bubbled during 2.5 hours into the resulting mixture which was kept between 6 C. and 22 C. with external cooling. The viscous reaction mixture was stirred an additional hour at 15 C. to 20 C. and then the excess sodium hydroxide was neutralized by the addition of concentrated hydrochloric acid (1070 grams) during one hour at 15 C. to 20 C.

The upper liquid layer was separated and distilled to obtain a product boiling from 60 C. to 92 C., which was washed, neutralized, freeze dried at 20 C. (341 grams) and fractionally distilled to give I (291 grams) b 74.7 C.-75.5C., d 1.47.

The low resolution proton nuclear magnetic resonance (NMR) spectrum of I is (1) a triplet centered at 6.18 p.p.m. for the methyl proton coupled (1.:72 Hz.) to the two methyl fluorines, (2) a triplet centered at 4.14 p.p.m. for the two propyl protons near oxygen coupled to two vicinal fluorines (J. =12.5 Hz.) and (3) a triplet of triplets centered at 5.81 p.p.m. for the other propyl proton coupled to two geminal fluorines (J. =52 Hz.) and two vicinal fluorines (J.'=4.5 Hz.). These line positions are relative to external tetramethyl silane.

EXAMPLE 2 1-ch1oro-2,2,3,3-tetrafluoropropyl difluoromethyl ether (II) Chlorine (23 grams) was bubbled into I (73 grams) at 5 C. to C. during about 6 hours with stirring and with irradiation from a sun lamp. Gas-liquid chromatographic (GLC) and proton NMR analyses indicated the product to be 65% II, 29% I and 6.3%

The product mixture (80 grams) was washed, neutralized, dried and fractionally distilled to give II (29.4 grams) b 94.6 C. to 954 C. of about 96.4% purity with HI as the major impurity.

The low resolution proton NMR spectrum of H is (1) a pair of doublets centered at 6.21 p.p.m. for the methyl proton coupled to the non-equivalent methyl fluorines (14:69-70 and 70-71 Hz.), (2) an apparent triplet centered at 5.96 p.p.m. for the propyl proton near oxygen coupled to two vicinal fluorines (J.=78 Hz.) and (3) a triplet of triplets centered at 5.87 p.p.m. for the other propyl hydrogen coupled to two geminal fluorines (1.: 52 Hz.) and two vicinal fluorines (J.=5 Hz.).

EXAMPLE 3 Difluoromethyl 1,2,2,3,3-pentafluoropropyl ether (IV) Chlorine (392 grams) was bubbled into I (914 grams) at about 15 C. during 6 hours with irradiation from a sun lamp and with stirring. Analysis by GLC indicated the product was 73% II, 15.7% III and 9.9% I. The product mixture was washed, neutralized, dried and fractionally distilled to remove I (in fractions b 74 C. to 95.2" C. totaling 165 grams) until the residue (900 grams) contained less than 0.1% I by GLC.

In the same manner, a similar residue (210 grams) was obtained from chlorine (122 grams) and I (284 grams).

The two residues were combined (1118 grams, 81.7%

II and 17.3% IH by GLC) and stirred as bromine trifiuoride (260 grams) was added at a rate to maintain a reaction temperature of about C. under reflux. After stirring overnight (about 16 hours), the remaining BrF was decomposed by cautious addition of water. The product was then freed of halogens, neutralized and dried to give crude IV (937 grams) containing an impurity V (essentially CHF OCFClCF CHF- derived from III and BrF which was not completely separated from IV by fractional distillation and had a longer retention time than IV on a 15% diisodecyl phthalate Chromasorb P column.

Crude IV (918 grams) in dry diethyleneglycol dimethylether (600 ml.) was treated with 0.9 molar lithium aluminum hydride in diethyleneglycol diethylether (266 ml.) at a temperature ranging from 25 C. to C. until V was no longer detectable by GLC. Distillation of IV from the reaction mixture under reduced pressure followed by fractional distillation gave IV (805 grams) [77 743 C. to 745 C., (1 1.55 grams/ml. of 99.4% purity of GLC.

The low resolution proton NMR spectrum of IV is 1) a triplet centered at 6.10 p.p.m. for the methyl proton coupled (J .=71 Hz.) to the two methyl fluorines, (2) a triplet of doublets centered at 5.68 p.p.m. for the propyl proton near oxygen coupled to a geminal fluorine (L -=55 Hz.) and two vicinal fluorines (J.=5.5 Hz.) and (3) a triplet of triplets centered at 5.63 p.p.m. for the other propyl proton coupled to two geminal fluorines (J.=53 Hz.) and two vicinal fluorines (J. =5 Hz.).

Various other examples and modifications of the foregoing examples will be apparent to those skilled in the art after reading the disclosure hereof without departing from the spirit and scope of the invention. All such further examples and modifications are included within the scope of the invention as defined in the appended claim.

What is claimed is:

1. The method of inducing anesthesia in animals which comprises administering by inhalation to an animal an effective amount for inducing anesthesia of difluoromethyl 1,2,2,3,3-pentafluoropropyl ether in admixture with oxygen in suitable amounts to support respiration.

References Cited UNITED STATES PATENTS 2,992,276 7/1961 Weinmaya 260-614 F 2,730,543 1/1956 Rendall et a1 260614 F 3,469,011 9/1969 Terrell 260614 F 2,533,133 1/1950 McBee et al. 260614 F X 2,567,569 1/1951 McBee et a1. 260-614 F X FOREIGN PATENTS 6511030 10/1965 Netherlands 260-614 F 1,122,847 8/1968 Great Britain 260-614 F 154,858 11/1963 U.S.S.R. 2606l4 F OTHER REFERENCES Yuminov et al.: J. Gen. Chem, U.S.S.R., vol. 37 (1967) PP. 350 354.

Park et al.: J.A.C.S., 78 (1956), pp. 1685-1686.

Lu et al.: Chem. Abst. 48 (1954), p. 1584b.

JEROME D. GOLDBERG, Primary Examiner 

